The overall goals of this research program is to establish the mechanisms leading to islet dysfunction in type 2 diabetes with a wider goal of facilitating rationale design of approaches designed to prevent or reverse type-2 diabetes. The islet in humans with type 2 diabetes mellitus (T2DM) is characterized by islet amyloid derived from islet amyloid polypeptide (IAPR), a protein that is co-expressed and secreted with insulin. Human IAPP (h-IAPP) has the propensity to form oligomers in solution. These oligomers cause non-selective ion channels in lipid membranes and can induce apoptosis. In the prior grant cycle we established that b-cell mass is decreased by ~65% in humans with T2DM, at least in part due to a ~10-fold increase in b-cell apoptosis. We also reported that b-cell mass is ~50% decreased in humans with impaired fasting glucose (IFG), implying that the loss of b-cell mass precedes development of hyperglycemia. We established h-IAPP transgenic rat (HIP) and mouse models which develop diabetes characterized by a progressive defect in b-cell mass due to increased b-cell apoptosis. Preliminary studies suggest h-IAPP toxicity is mediated through endoplasmic reticulum stress, and that this is active in patients with T2DM. In the proposed studies we seek to address the following questions. 1) Is b-cell apoptosis increased in humans with IFG? 2) What is the mechanism of h-IAPP induced b-cell apoptosis, and is this mechanism active in humans with IFG and T2DM? 3) Do toxic IAPP oligomers form intracellularly and cause endoplasmic reticulum membrane leakage? 4) Can we prevent development of diabetes in the HIP (h-IAPP transgenic) rat? This program of studies would allow us to shed light into the underlying cause of loss of b-cells in humans, and to establish a rationale approach to preventing this.